New PET-Scan Probe Could Enable Better Monitoring of Immune Responses

Researchers at UCLA have reported developing a new molecular beacon for positron emission tomography (PET) scanners that could allow clinicians to image and track key immune-system cells noninvasively.

“We see it as being useful for autoimmune and maybe even inflammatory disorders,” says Caius Radu of UCLA’s Crump Institute for Molecular Imaging, “and potentially also to monitor cancer immune therapy approaches” including cancer vaccines.

As reported online June 8 in Nature Medicine, Radu and colleagues devised a probe based on the standard chemotherapy drug gemcitabine. The drug mimics a basic building block of DNA to gain entry to cells; once inside, it blocks the DNA synthesis needed for cell division as if the drug were a bad tooth on a zipper. Sensing the damage, affected cells typically self-destruct. Tumor cells are most often affected because they undergo cell division so frequently, but other quick-dividing cells, especially immune cells, also are vulnerable.

That vulnerability led Radu and his colleagues to modify gemcitabine into a molecule called fluoroarabinofuranosyl cytosine (FAC). It is less toxic to DNA—and apparently harmless at the tiny doses used for imaging—but is still easily taken up by many classes of fast-dividing cells, particularly those that have activated a biochemical program called the “DNA salvage pathway.” Immune T cells, macrophages and lymph glands tend to rely heavily on this pathway when called into action by an infection or tumor. [His work is funded in part by the Dana Foundation.]

How PET works

PET probes are usually injected into a patient’s bloodstream a few minutes prior to imaging; the molecules then quickly travel and infiltrate their target cells. Probe molecules carry beacons in the form of unstable radioisotopes, most commonly fluorine-18, which is a good source of the positrons that PET scanners are designed to detect.

A positron is the antimatter counterpart of an electron; certain radioisotopes, including fluorine-18, emit such positrons when they experience the energy drops of ordinary radioactive decay. Within a few millimeters of its origin, a positron inevitably encounters an electron, and in a flash the matter-antimatter collision yields a pair of gamma-ray photons speeding in opposite directions. The PET scanner’s ring-shaped detector is designed to sense the near-simultaneous impacts of these photons and its software can calculate the origin point for each pair, thus marking the approximate location of each beacon in three dimensions.

Probes wanted

PET technology has been around for three decades, but only a few PET probes have been developed, in part because the most commonly used probe, fluorodeoxyglucose (FDG), has been so versatile. FDG, which also incorporates fluorine-18, mimics the essential sugar molecule glucose and thus tends to go wherever cellular metabolic activity is most intense.

“It is cheap to make, anybody can make it, and it is extremely useful in cancer especially,” says Radu. FDG mimics glucose but can’t be metabolized like glucose, so it accumulates in cells, and does so most swiftly in those with high glucose uptake, including many cancer cells and also brain cells.

But FDG isn’t particularly good at labeling immune cells, which is why Radu and his colleagues sought to develop FAC. In their Nature Medicine paper, they report using FAC and a micro-PET system to detect the activation of lymphoid tissue and immune cells in mice under several experimentally induced conditions, including an autoimmune reaction and an anti-tumor immune reaction.

“There clearly are tumor-specific effects of manipulating the immune system,” says Kevin Shannon, a molecular oncologist at the University of California, San Francisco. But traditionally, he notes, those effects have been harder to quantify than following metabolic activity. “And one way of beginning to address that and the entire role of the microenvironment in cancer and even rheumatic disease is with some of these probes that light up cells that are metabolically active or infiltrating.”

The researchers continue to refine their FAC techniques. Ultimately, Radu says, when they have developed a repertoire of probes such as FDG and FAC, “we’ll be able to get what’s called a metabolic response profile, a functional kind of imaging profile that enables us to determine very quickly how well treatments are working in the body.”